Pressure sensitive adhesives (PSA) have been widely used in various fields for holding, protecting, sealing, and masking purposes. Application of PSA to the medical area is an important application field and the subject of considerable investigation. One recent application to the medical field is to the area of transdermal (and less so, transmucosal) drug delivery systems. In the rest of this specification, unless the context requires otherwise, the term "transdermal" will refer collectively to transdermal and transmucosal and the term "skin" will refer respectively to skin or mucosa depending on whether a transdermal or transmucosal device is under consideration. In addition to the general requirements for PSAs for general use, transdermal delivery systems require that PSAs be nonirritating to the skin, be physically and chemically compatible with the drug(s) being delivered therethrough, and be moisture resistant. PSAs must also adhere well to the skin, provide intimate contact of the transdermal system with the skin surface during application of the transdermal system, and leave no residue upon removal.
Transdermal drug delivery systems can be divided into two types: (a) reservoir systems and (b) matrix or monolithic systems. PSAs are key components in both types of systems. Therefore, a PSA that meets the aforementioned requirements and at the same time is easily formulated and processed for manufacture of transdermal drug delivery systems would play a critical role in the design, development, and production of such systems and has been long sought after.
Since the permeation of drugs through the skin is limited by the molecular weight, partition coefficient, and solubility of the drug being administered as well as the skin structure itself, transdermal drug delivery systems have frequently been limited to certain drugs that possess the favored physico-chemical properties for skin permeation. As such, permeation enhancers have been used to raise the flux of various drugs through the skin and enable transdermal drug delivery systems to achieve therapeutic blood levels of a much wider range of drugs. These enhancers extend the availability of the transdermal route to a wide range of bioactive agents including hydrophilic drugs, peptides, etc. Unfortunately, the introduction of the enhancer often simultaneously introduced problems relating to the adhesives used in the system. These have included: failure of the integrity of the system, loss of tack of PSA, and loss of cohesive strength.
The major PSAs that have been evaluated and used in transdermal systems are polyisobutylene, polyacrylates, and polydimethylsiloxanes. Acrylic type PSAs have served as adhesives in transdermal commercial products. Alkyl acrylates are tacky and pressure-sensitive, and therefore do not require the addition of tackifying agents or plasticizers. This type of PSA is also non-oxidizing, and, therefore, does not need any anti-oxidant. Organic silicones have been considered biocompatible and oxygen permeable. From the above, it is apparent that a PSA composed of acrylic and organic silicone types of polymers and retaining the best properties of each would be highly desirable for use in medical, specifically transdermal drug delivery system, applications.
U.S. Pat. Nos. 2,884,126 (Ulrich, 1959), 2,973,286 (Ulrich, 1961), 3,121,021 (Copeland, 1964) 3,321,451 (Gander, 1967), 3,475,363 (Gander, 1969), 3,998,997 (Mowdood et al, 1976), and 4,374,883 (Winslow, 1983) describe copolymers of acrylates and acrylic acid as PSAs. U.S. Pat. No. 4,432,848 (Korpman, 1984) describes a PSA based on A-B-A copolymer of alkenylarene and isoprene. U.S. Pat. Nos. 4,693,776 (Krampe et al, 1987) and 4,732,808 (Krampe et al, 1988) describe copolymers of acrylic acid, alkyl acrylate, and methacrylate terminated macromers and their use for skin adhesion. In U.S. Pat. No. 3,532,652 (Zang, 1970), copolymers of alkyl acrylate and vinyl or acrylic monomers with functional groups, such as carboxyl, hydroxyl, amino, as well as amido and substituted amido, crosslinked with isocyanate terminated polymers were claimed as PSAs. U.S. Pat. Nos. 4,737,559 (Kellen et al, 1988) and 4,847,137 (Kellen et al, 1989) describe UV-polymerization of acrylates with mono-ethylenically unsaturated aromatic ketone monomer as a photocrosslinker in PSAs. U.S. Pat. No. 4,714,655 (Bordolol et al, 1987) describes UV-polymerization for PSAs containing heat sensitive materials from commercially available prepolymers. Transdermal application is specifically referred to. U.S. Pat. Nos. 4,156,035 (Tsao et al, 1979) and 4,786,552 (Sasaki et al, 1988) discuss UV-curable compositions and processes. These and other UV-curing processes offer significant advantages over other (non-UV) curing methods, in particular, freedom from use of organic solvents in preparation and the concomitant environmental disposal problems associated therewith, reduction in energy utilization to carry out the polymerization, and the freedom to incorporate heat sensitive materials into the composition.
In U.S. Pat. No. 4,140,115 (Schonfeld, 1979) an organic silicone monomer, 3-methacryloxypropyltrimethoxysilane, was used as a cross-linking agent in very small amounts (0.01-0.05 parts of total monomers by weight). Terpolymers or tetrapolymers of acrylate/methacrylate and 3-methacryloxypropyl tris(trimethylsiloxy) silane have been disclosed in U.S. Pat. No. 4,665,145 (Yokota et al, 1987), Japanese Patent 01249872 (Tamada et al, 1989) and Japanese Patent 63137934 (Okido et al, 1988).
It has been known that a PSA should have a balance of cohesive and adhesive strength to perform appropriately in a transdermal drug delivery system. Such a balance has been attempted by incorporating two or more components with different properties by blending polymers or in some instances by copolymerization. The hoped for result is that the desired balance is achieved (the beneficial properties of the components are retained) while the disadvantages of the components are overcome.
Poly(alkyl acrylate)s, especially poly(ethylhexyl acrylate), are generally known as tacky, low glass transition temperature polymers. By incorporating a component with a higher glass transition temperature and higher cohesive strength, one would hope for a copolymer which would exhibit more favorable properties suitable for exploitation in a transdermal drug delivery system.
U.S. Pat. Nos. 5,010,141 (Mueller, 1991) and 5,115,056 (Mueller et al, 1992) discloses the use of siloxy silanes as comonomers in the preparation of contact lenses, a utility which would lead away from the notion that the compositions containing the siloxy silanes in any significant proportion would have adhesive properties.
All of the foregoing U.S. Patents are hereby incorporated by reference into this specification, the same as if the details thereof had been repeated here verbatim.